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CROI 2014: Chronic Inflammation - Can Anything Be Done?

The Role of Traditional Risk Factors. Many factors play a role in chronic inflammation in HIV. The immune response to HIV itself, microbial translocation, co-infections such as CMV or HCV, toxic effects of antiviral drugs and incomplete reconstitution of down-regulatory immune mechanisms all may play a role. In the general population, aging, obesity, dyslipidemia, dysglycemia and smoking are associated with elevation of inflammatory markers. These traditional risk factors may also play a role in the chronic inflammation seen in HIV-infected individuals. Krishnan et al [1] measured interleukin-6 (IL-6), soluble CD14, IP-10, soluble TNF receptor I (sTNFRI) and II, (sTFNRII) and d-dimer and assessed traditional risk factors in 315 HIV-infected patients virologically controlled on ART. In an adjusted analysis, older age correlated with all 6 markers. Smoking correlated with IL-6, sCD14, sTNFRI & II and fasting glucose correlated with IL-6 and sTNFRII. Obesity, as assessed by waist circumference, waist-hip ratio, and BMI showed correlations with various combinations of IL-6, sCD14 and sTNFRI or II. A related study measured sCD14 and d-dimer in 689 participants in the SUN study cohort and assessed smoking and alcohol use by questionnaire [2]. Smoking was strongly correlated with levels of sCD14 levels. Heavy alcohol use (5 or more drinks on one or more occasions in a month) was associated with higher d-dimer levels. These studies suggest that in addition to HIV-related mechanisms, traditional risk factors for chronic inflammation also are important in HIV-infected individuals. Many of these risk factors are potentially modifiable and should be addressed clinically whenever possible.

Statins. Statins are widely used in the general population to lower cholesterol and reduce the risk of subsequent cardiovascular (CVD) disease. Because dyslipidemia is common in HIV, statins are also often used in this population for the same indication. However, the effect of statins on CVD risk goes beyond lipid lowering. Statins have anti-inflammatory effects that contribute to CVD reduction, although the precise mechanism is not certain. Since both CVD and chronic inflammation are increased in HIV, statins are a particularly attractive candidate drug class to reduce inflammation in this population. They have the additional benefit of wide availability and a very well known safety profile during long-term administration.

Funderburg et al [3] reported 48 week results of a randomized trial comparing rosuvastatin 10 mg daily and placebo. Eligible participants (n=147) were on stable ART with elevated T-cell activation or hsCRP and LDL cholesterol <130 mg/dL at baseline. A large panel of immune activation and inflammatory markers were studied. Most showed declines from baseline in both groups. Declines were significantly greater in the rosuvastatin group for the monocyte activation markers sCD14 and CD16+/tissue factor+/CD14dim monocytes, IP-10, the vascular inflammation marker Lp-PLA2 and various cellular markers of CD4 and CD8 activation. Although declines in hsCRP have been seen in many studies of statins in HIV-negative populations, hsCRP did not decline in this study.

Exercise. Moderate intensity exercise appeared beneficial in a study of 49 sedentary, ART-treated patients [4]. Participants were enrolled in an exercise program that included one hour of brisk walking with or without 30 minutes of circuit training exercise 3 times weekly for 12 weeks. In a subset of 25 individuals who completed the program and had inflammatory marker data available, d-dimer, IL-6, hsCRP, IL-18, myostatin, and CD4 and CD8 activation markers (HLA-DR+, CD38+) all declined significantly, while sCD14 did not. Additional benefits included significant declines in BMI, waist circumference, total and LDL cholesterol. Although this intervention appeared to provide broad reductions in inflammatory markers for those completing the program, 14/49 (29%) either dropped out or had a low participation rate. Also, it was not clear how much reduction was attributable to walking alone vs. walking plus circuit training.

1. Krishnan S, Bosch RJ, Rodriguez B, et al. Correlates of Inflammatory Markers After One Year of Suppressive Antiretroviral Treatment (ART). Abstract 757. CROI 2014, Boston, MA, March 3-6, 2014.
2. Cioe PA, Baker J, John Hammer J, et al. Soluble CD14 and D-Dimer Are Associated With Smoking and Heavy Alcohol Use in HIV-Infected Adults. Abstract 732. CROI 2014, Boston, MA, March 3-6, 2014.
3. Funderburg N, Clagett B, Jiang Y, et al. Rosuvastatin Reduces Immune Activation and Inflammation in Treated HIV Infection. Abstract 335. CROI 2014, Boston, MA, March 3-6, 2014.
4. Longo V, Bonato M, Bossolasco S, et al. Brisk Walking Improves Inflammatory Markers in cART-Treated Patients. Abstract 763. CROI 2014, Boston, MA, March 3-6, 2014.

Source: Reporting from Boston for PRN News: David H Shepp, MD